Jeffery Alexander, DPM FACFAS Rush University Medical Center Chicago, IL

1. The Use of Topical Flurbiprofen Cream to Treat Plantar Fasciitis, a Randomized, Prospective Trial vs Oral NSAID Therapy Jeffery Alexander, DPM FACFAS Rush University Medical Center Chicago, IL

2. Plantar Fasciitis • Most common cause of plantar heel pain • Affects up to 10% of US population • Accounts for >600,000 patient visits annually in the US

3. Plantar Fasciitis • Inflammation and pain along the plantar fascia - the tissue band that supports the arch on the bottom of the foot • Pain is usually found on the bottom of the heel at the point where the plantar fascia attaches to the heel bone • Becomes chronic in 5-10% of all patients • Is not necessarily associated with a heel spur • Over 90% resolve with conservative treatment

4. Plantar Fasciitis Symptoms • Pain on standing, especially after periods of inactivity or sleep • Pain subsides after a period of time, returns with activity after rest (post static dyskinesia) • Pain related to footwear – can be worse in flat shoes with no support • Radiating pain to the arch and/or toes • In later stages, pain may persist/progress throughout the day • Pain varies in character: dull aching, “bruised” feeling. Burning or tingling, numbness, or sharp pain, may indicate local nerve irritation

5. Plantar Fasciitis Risk Factors • Biomechanical abnormalities • Overly tight calf muscle • Poor shoe choices • Weight gain • Barefoot walking • Work surface

6. Plantar Fasciitis Treatment- Overview • Mechanical – treat the cause • Anti-inflammatory – treat the pain • Neither done in isolation

7. Plantar Fasciitis Treatment • Stretching, shoe modifications, avoid walking barefoot • Icing and rest • Night or resting splint • Supplemental arch support (OTC vs. custom orthotics) • Anti-inflammatory medication • Steroid injections • Physical therapy • If conservative measures fail, surgery is an option

8. Other options for heel pain • Over 90% of heel pain patients respond to initial therapies within a relatively short period of time • For unresponsive cases, options include: • Minimally invasive procedures like ESWT (Extracorporeal Shock Wave Therapy) • Autologous Platelet Concentrate (APC) injection • Surgical procedures, open or endoscopic • Cryosurgery • Radiofrequency techniques

9. What Does Research Tell Us About Treatment? • Approximately 80% of patients treated conservatively had complete resolution of their symptoms1 • No evidence strongly supports the effectiveness of any treatment for plantar fasciitis • Cochrane Review2 showed corticosteroid injections improved plantar fasciitis symptoms at one month but not at six months when compared to placebo

10. Research Specific to NSAIDs and Plantar Fasciitis • Treatment protocols in most studies include ice and NSAID therapy. No studies have specifically examined their effectiveness. 3 • Although no data supports the use of NSAIDs or ice, their effectiveness in managing other musculoskeletal conditions makes them reasonable choices for adjunctive therapy 4 5

11. Complications of Oral NSAID Use • High incidence events • GI disturbances • Nausea, Vomiting, Dyspepsia • Potential Serious Events • GI ulcerationor bleeding • Hypertension • Cardiovascular events • Acute renal impairment • Hepatotoxicity

12. Oral NSAIDs - Cost of Adverse Events • In 1983, it cost an estimated $8.6 billion to treat arthritis in the USA • It cost an additional $3.9 billion to treating gastrointestinal side effects of NSAIDs for a total cost of 12.5 billion. • Conclusion: 30% of medical costs when using oral NSAIDs can be attributed to gastrointestinal side effects.

13. Are Oral NSAIDs Still the Answer? • The authors sought to determine if alternative therapies could offer equal efficacy with improved side effect profile • With advancements in available transdermal carrier agents, topical NSAID formulations were selected

14. Background • Topical anti-inflammatories7,9: • Advantages: Little to no systemic absorption, no GI upset, considered safe for renally impaired, good for patients that do not want to take more medications. • Disadvantages: Application can be difficult (locations and flexibility of patient), cost, variability in penetration/absorption. • Recent study showed significantly higher concentrations of flurbiprofen in tendon, muscle and periosteal tissues when administered through a patch vs. oral, however, there was a large degree of variability between individuals.8 • Purpose: Determine if topical anti-inflammatories can be an equally effective alternative to oral NSAIDs.

15. Effect of Compounded Topical Anti-Inflammatory Cream (Flurbiprofen) vs PO NSAID (Ibuprofen) in the Treatment of Plantar Fasciitis- A Pilot Study Jeffey Alexander, DPM Gene Choi, DPM

16. Methods • Power analysis, study designed to be a non-inferiority study • 60 patients with unilateral plantar fasciitis were randomized into 2 groups: (40 experimental, 20 control) • Exclusion criteria: Previous professional treatment, suspicion of nerve involvement (+ tinels/valleix sign, tarsal tunnel syndrome), contralateral pain, h/o NSAID intolerance (GI upset, hypersensitivity), renal impairment, CV disease, cortisone injections, failure to comply. • Inclusion criteria: Symptomatic for > 4 weeks and not resolving. • Age: ranged from 29 – 79 (Avg: Experimental 55.7, Control 59.5) • All patients instructed to reduce activity, ice (20min 3x/day), perform stretching exercises (written and visual instructions), and use standard OTC orthotics.

17. Methods • Experimental group: Compounded topical anti-inflammatory medication containing: Flurbiprofen 10%, Baclofen 2% and Lidocaine 5% in a Lipoderm base with pentoxifylline 3%. • Control group: Ibuprofen 800mg PO TID • Record weekly pain scores using VAS • Follow up weekly for 3 months.

18. Data • Patients’ weekly pain scores were rated using the visual analog pain scale (VAS) on initial visit and subsequent weekly follow up visits. • Experimental group: • Avg: 4.3667 point decrease in pain. (σ: 1.846) • Avg: 65.3% (0.6526) relief in pain (σ: 0.1945) • Control group: • Avg: 3.6 point decrease in pain. (σ: 0.5477) • Avg: 60.9% (0.6086) relief in pain (σ: 0.1132) • Reported adverse events • Topical: Texture complaints (2/40) • Oral: GI Upset (4/20)

19. Statistics F-test: % Change in VAS • P = 0.30559 • Accept Ho: No significant difference between oral vs. topical. F-test: Mean differences in VAS • P = 0.03052 • Reject Ho: Topical significantly better relief than oral. 19

20. Statistics • ANOVA: Mean differences in VAS • P = 0.37977 • Accept Ho: No significant difference between oral vs. topical. • ANOVA: % Change in VAS • P = 0.64041 • Accept Ho: No significant difference between oral vs. topical. 20

21. Statistics • T-test: Mean differences in VAS • P = 0.16975 • Accept Ho: No significant difference between oral vs. topical. • T-test: % Change in VAS • P = 0.54811 • Accept Ho: No significant difference between oral vs. topical. 21

22. Results • Topical compounded anti-inflammatory cream with flurbiprofen is NON INFERIOR to oral NSAIDs in treating plantar fasciitis. • Adverse Events: • Topical Cream: 5% (2/40) complained that the cream was “sticky” (1/40) or “gritty” (1/40), but both of these patients continued to use it because of the efficacy • Oral NSAID: 20% (4/20) with GI Upset, but none of these patients discontinued therapy

23. Where Does the NSAID Go? 6 • Oral vs. Topical NSAID • Comparison of Median Maximum Concentrations, cMax, of NSAID in Joint Tissue after Topical and Oral Administration • NSAID is Maximized in Cartilage and Meniscus and Minimized in Plasma After Topical Application Rolf C, et al. Intra-articular absorption and distribution of ketoprofen after topical plaster application and oral intake in 100 patients undergoing knee arthroscopy. Rheumatology (1999); 38:564-567.

24. What about Flurbiprofen and Plantar Fasciitis? Better penetration into soft tissues in topical formulations than oral 8 • All percents are tissue:plasma concentrations • Tendon • Oral 7% • Topical 160% • Muscle • Oral 3% • Topical 77% • Periosteum • Oral 9% • Topical 65% • Bone • Oral 4% • Topical 11% 8 Kai S, Kondo E, Kawaguchi Y, et al. Flurbiprofen concentration in soft tissue is higher after topical application than after oral administration. British J Clinical Pharm. 2012. 75:3;799-804.

25. Advantages of Topicals Improved Safety Profile • Avoids GI 1st pass metabolism • Traditionally 25% GI side effects using PO NSAIDs • Most topical components do not reach systemic levels • Finch et al (2009)- Ketamime levels were below detectable limits • ME Lynch et al (2003)- Blood levels showed no significant absorption of Amitriptyline or Ketamime • No specific absorption of either agent after 7 days of treatment • 15% of topical NSAIDs is thought to be absorbed systemically

26. Discussion • Limitations: • Small sample size, unable to appreciate safety advantages of topical formulations. • Limited follow up. • Future research: Blinded prospective study comparing the topical compound cream with a placebo cream.

27. References • 1 Wolgin M, Cook C, Graham C, Mauldin D. Conservative treatment of plantar heel pain: long term follow up. Foot Ankle Int. 1994:15:97-102. • 2 Crawford F, Thomson C. Interventions for treating heel pain. Cochrane Database Syst Rev. 2003;(3):CD000416. • 3 Buchbinder R. Clincal Practice. Plantar Fasciitis. New Engl J Med. 2004;350:2159-66. • 4 Pfeffer G, Bacchetti P, Deland J, Lewis A, Anderson R, Davis W. Comparison of custom and prefabricated orthoses in the initial treatment of proximal plantar fasciitis. Foot Ankle Int. 1999;20:214-21. • 5 DiGiovanni BF, Nawoczenski DA, Lintal ME, Moore EA, Murray JC, Wilding GE, et al. Tissue-specific plantar fasciastretching exercise enhances outcomes in patients with chronic heel pain. A prospective, randomized study. J Bone Joint Surg Am. 2003;85-A:1270-7. • 6 Rolf C, et al. Intra-articular absorption and distribution of ketoprofen after topical plaster application and oral intake in 100 patients undergoing knee arthroscopy. Rheumatology (1999); 38:564-567.

28. Referenced 7 Jorge LL, Feres CC, Teles VE. Topical preparations for pain relief: efficacy and patient adherence. J Pain Research. 2011. 4;11-24. 8 Kai S, Kondo E, Kawaguchi Y, et al. Flurbiprofen concentration in soft tissue is higher after topical application than after oral administration. British J Clinical Pharm. 2012. 75:3;799-804. 9Pandey MS, Belgamwar VS, Surana SJ. Topical delivery of flurbiprofen from pluronic lecithin organogel. Indian J Pharm Sci. 2009. 71;87-90. 10 Dexter F, Chestnut DH. Analysis of statistical tests to compare visual analog scale measurements among groups. Anesthesiology. 1995. 82:896-902.